WO2017150549A1 - Médicament radiomarqué - Google Patents

Médicament radiomarqué Download PDF

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WO2017150549A1
WO2017150549A1 PCT/JP2017/007875 JP2017007875W WO2017150549A1 WO 2017150549 A1 WO2017150549 A1 WO 2017150549A1 JP 2017007875 W JP2017007875 W JP 2017007875W WO 2017150549 A1 WO2017150549 A1 WO 2017150549A1
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group
acceptable salt
nota
compound
fab
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PCT/JP2017/007875
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English (en)
Japanese (ja)
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泰 荒野
知也 上原
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国立大学法人 千葉大学
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Priority to JP2018503339A priority Critical patent/JP6966741B2/ja
Priority to EP17760014.5A priority patent/EP3424940A4/fr
Priority to KR1020187025332A priority patent/KR20180118658A/ko
Priority to US16/081,141 priority patent/US10960089B2/en
Priority to CN201780014525.2A priority patent/CN108699108B/zh
Publication of WO2017150549A1 publication Critical patent/WO2017150549A1/fr
Priority to HK18116502.7A priority patent/HK1257541A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A61K51/1066—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell being from skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A61K51/1072—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell being from the reproductive system, e.g. ovaria, uterus, testes or prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to a novel compound, a radiolabeled drug containing the same, a drug for preparing the radiolabeled drug, and the like.
  • Radiolabeled drugs such as single photon emission tomography (hereinafter simply referred to as “SPECT”), positron emission tomography (hereinafter also simply referred to as “PET”), etc. using radiolabeled drugs
  • SPECT single photon emission tomography
  • PET positron emission tomography
  • Various radionuclides are used for these radiological imaging.
  • gallium-67 ( 67 Ga) is used for SPECT
  • gallium-68 ( 68 Ga) is used for PET.
  • 68 Ga has been attracting attention in recent years because it can be eluted from a generator using germanium- 68 .
  • a peptide having a low molecular weight such as a low molecular weight antibody having a high blood clearance is used as a labeling matrix.
  • RI radioisotope
  • renal accumulation Accumulation of radioactivity in the kidney (hereinafter also referred to as “renal accumulation”) is that the radiolabeled metabolite produced after the RI-labeled low-molecular peptide is taken up by the kidney, transported to the lysosome, and metabolized remains in the kidney. It is based on that.
  • Non-Patent Document 1 the radioactive gallium-labeled drug described in Non-Patent Document 1 indicates that 67 Ga-NOTA-Bn-Met (see the formula in the specification) is excreted from the kidney lysosome fraction into the urine. Utilizing and releasing the radioactive gallium-labeled antibody fragment into the renal tissue and then releasing 67 Ga-NOTA-Bn-Met within the lysosome significantly reduces renal accumulation compared to conventional methods.
  • the present invention relates to a compound or the like from which a radiolabeled drug capable of reducing accumulation in the kidney from the early stage of administration can be obtained.
  • a compound represented by the following formula (1) or a pharmacologically acceptable salt thereof [Where, A 1 is an amino acid residue; m is an integer from 0 to 3, A 2 is an amino acid residue having an amino group or a carboxy group in the side chain; A 3 is an amino acid residue; n is an integer from 0 to 3, R 1 is a group having a functional group that binds to the amino group or carboxy group of the side chain of A 2 and can bind to the polypeptide or a linking group thereof; R 2 is each independently a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms.
  • R 1 may form a C 3-10 heterocyclic group containing the nitrogen atom of the amino group of the side chain of A 2 as one of the ring constituent atoms.
  • [2] A compound obtained by binding a target molecule recognition element to the compound according to [1] above or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable salt thereof.
  • [3] A metal having one type of metal selected from a radioactive metal and a radioactive atom-labeled metal, and a compound or a pharmaceutically acceptable salt thereof according to [1] or [2] coordinated to the metal Complex compound or pharmacologically acceptable salt thereof.
  • a drug for preparing a radiolabeled drug comprising the compound according to [1] or [2] above or a pharmacologically acceptable salt thereof.
  • a radiolabeled drug comprising the metal complex compound of [3] above or a pharmacologically acceptable salt thereof.
  • a target molecule recognition element is added to the compound according to [1] or a pharmacologically acceptable salt thereof, or the compound according to [1] or a pharmacologically acceptable salt thereof.
  • a kit comprising a compound obtained by binding, or a pharmaceutically acceptable salt thereof, and a drug containing one metal selected from a radioactive metal and a radioactive atom-labeled metal, as separate packaging units.
  • the present invention it is possible to provide a compound or the like capable of obtaining a radiolabeled drug that can reduce accumulation in the kidney from the early stage of administration.
  • FIG. 1 shows the results of studies on the stability of radioactive metal-labeled Fab in mouse plasma.
  • FIG. 2 shows the time course of (a) renal radioactivity (time-radiation dose curve in the kidney) and (b) renal blood ratio of radioactivity.
  • FIG. 3 shows urinary radioactivity up to 6 hours after administration of (a) 67 Ga-NOTA-MVK-Fab, (b) 67 Ga-NOTA-MI-Fab, and (c) 67 Ga-NOTA-SCN-Fab. The analysis result by SE-HPLC is shown.
  • FIG. 4 shows urinary radioactivity up to 6 hours after administration of (a) 67 Ga-NOTA-MVK-Fab, (b) 67 Ga-NOTA-MI-Fab, and (c) 67 Ga-NOTA-SCN-Fab.
  • FIG. 5 shows the tumor kidney ratio of 67 Ga-NOTA-MVK-Fab, 67 Ga-NOTA-MI-Fab and 67 Ga-NOTA-SCN-Fab.
  • FIG. 6 shows SPECT / CT images 3 hours after each 67 Ga-labeled Fab solution was administered to SY subcutaneous tumor model mice.
  • FIG. 7 shows that 64 Cu-NOTA-MVK-Fab (shown as 64 Cu-MVK-Fab in the figure) and 64 Cu-NOTA-Fab (shown as 64 Cu-SCN-Fab in the figure) were administered to normal mice. Sometimes shows PET images after 3 hours.
  • Compound (1) etc. The compound of the present invention or a pharmacologically acceptable salt thereof (hereinafter also simply referred to as “compound (1) etc.”) is represented by the following formula (1).
  • a 1 is an amino acid residue
  • m is an integer from 0 to 3
  • a 2 is an amino acid residue having an amino group or a carboxy group in the side chain
  • a 3 is an amino acid residue
  • n is an integer from 0 to 3
  • R 1 is a group having a functional group that binds to the amino group or carboxy group on the side chain of A 2 and can bind to the target molecule recognition element or its linking group, or the amino group or carboxy group on the side chain of A 2
  • a hydrogen atom of R 2 is each independently a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms.
  • R 1 may form a C 3-10 heterocyclic group containing the nitrogen atom of the amino group of the side chain of A 2 as one of the ring constituent atoms.
  • the radiolabeled drug of the present invention since the radiolabeled drug of the present invention has a target molecule recognition element, it can specifically bind to the target site, and therefore accumulates efficiently at the target site. Due to such properties, the radiolabeled drug of the present invention can improve the sensitivity and accuracy of radiographic diagnosis.
  • a 1 is preferably a fat-soluble amino acid residue from the viewpoint of reducing accumulation in the kidney from the early stage of administration, and more preferably valine, leucine. From the viewpoint of making the effect of reducing accumulation in the kidney from the early stage of administration more preferable, it is more preferably a residue of valine.
  • m is an integer of 0 to 3, preferably 1.
  • a 2 is an amino acid residue having an amino group or a carboxy group in the side chain from the viewpoint of introducing a functional group capable of binding to the polypeptide or a linking group thereof into the side chain of the amino acid sequence, preferably lysine, Ornithine, arginine, aspartic acid or glutamic acid residue, more preferably lysine, ornithine or arginine residue, more preferably lysine residue.
  • a 3 may have other amino acid residues. Any amino acid is used as A 3 .
  • n is an integer of 0 to 3, preferably 0.
  • R 1 is a group having a target molecular recognition element or functional group capable of bonding with the coupling group or a hydrogen atom of the amino group or carboxy group of the side chain of A 2, the amino group of the side chain of A 2 or It binds to the carboxy group.
  • R 1 may form a C 3-10 heterocyclic group containing the nitrogen atom of the amino group of the side chain of A 2 as one of the ring constituent atoms.
  • R 1 functions as a spacer and can bind a target molecule recognition element such as a polypeptide to the compound of the present invention via a functional group.
  • R 1 can bind the compound of the present invention and the polypeptide without chemically modifying the amino acid sequence terminal by binding to the amino group or carboxy group of the side chain of A 2 .
  • R 1 may be bonded to the nitrogen atom of the amino group in the side chain, or may form an ester bond with the carboxy group in the side chain.
  • the functional group capable of binding to the target molecule recognition element of R 1 or a linking group thereof is not particularly limited, but examples thereof include a carboxy group or an active ester thereof; a group having a C ⁇ C bond such as a maleimide group or an acryloyl group; , At least one functional group selected from the group consisting of an isothiocyanate group and an amino group (hereinafter also referred to as “functional group a”).
  • the carboxy group active ester include a chloroacetyl group, a bromoacetyl group, and an iodoacetyl group.
  • the functional group a is preferably a group having a C ⁇ C bond or a carbamoyl group.
  • the total number of carbon atoms of R 1 is not particularly limited, but is preferably 1 or more, more preferably 2 or more, still more preferably 3 or more, and preferably 20 or less, more preferably 10 or less, and still more preferably 8 It is as follows.
  • R 1 include an acyl group having 2 to 20 carbon atoms having a functional group a, an alkyl group having 2 to 20 carbon atoms having a functional group a, and an alkyl group having 2 to 20 carbon atoms having a functional group a.
  • Examples thereof include a carbamoyl group and an alkylthiocarbamoyl group having 2 to 20 carbon atoms and having a functional group a.
  • the heterocyclic group is preferably a maleimide group.
  • the number of carbon atoms in the heterocyclic group is preferably 3 to 10, more preferably 3 to 5, and even more preferably 4 or 5.
  • R 1 may be a hydrogen atom of an amino group or a carboxy group in the side chain of A 2 . That is, the amino group or carboxy group of A 2 may not be modified.
  • a heterocyclic group having 3 to 10 carbon atoms including the nitrogen atom of the amino group of the side chain of A 2 is preferable as one of the ring constituent atoms, and the side chain of A 2 is preferable as one of the ring constituent atoms.
  • a maleimide group containing a nitrogen atom of an amino group is more preferred.
  • R 2 is each independently a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms.
  • the hydrocarbon group for R 2 is not particularly limited, but is preferably a hydrocarbon group used as a protecting group, and examples thereof include a methyl group, an ethyl group, a t-butyl group, and a benzyl group.
  • a hydrogen atom is preferable.
  • R 2 is independently a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms
  • R 3 is a hydrogen atom or a methyl group
  • R 4 and R 5 are each independently hydrogen.
  • R 4 and R 5 may form a heterocyclic ring containing an adjacent nitrogen atom, in which case the formula:
  • R 4 and R 5 are preferably an acyl group having 2 to 20 carbon atoms and having a functional group a, and more preferably an acyl group having 3 to 6 carbon atoms having a carbamoyl group.
  • Examples of the acyl group having 3 to 6 carbon atoms having a carbamoyl group include, for example, the formula: —C ( ⁇ O) (CH 2 ) a ( ⁇ O) NH 2 wherein a is an integer of 1 to 4. . The group represented by this is mentioned.
  • Preferred specific examples of the compound (1) of the present invention include the following compounds 1-1 to 1-4.
  • Compound (1) and the like of the present invention may be a pharmacologically acceptable salt of the above compound.
  • pharmacologically acceptable salts include acid addition salts and base addition salts.
  • the acid addition salt may be either an inorganic acid salt or an organic acid salt.
  • the inorganic acid salt include hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate and the like.
  • Organic salts include, for example, citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate Examples thereof include salts and p-toluenesulfonate.
  • the base addition salt may be either an inorganic base salt or an organic base salt.
  • the inorganic base salt include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.
  • organic base salt include triethylammonium salt, triethanolammonium salt, pyridinium salt, diisopropylammonium salt and the like.
  • the compound (2) or the like of the present invention is a compound obtained by binding a target molecule recognition element to the compound (1) or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable salt thereof.
  • the target molecule recognition element may be bonded to the compound (1) or a pharmacologically acceptable salt thereof via a linking group, or may be directly bonded. Examples of the linking group include iminothiol derived from 2-iminothiolane.
  • target molecule recognition element is a molecule, a substituent, a functional group, or an atomic group capable of recognizing a target molecule such as binding to the target molecule in vivo.
  • the target molecule recognition element include polypeptides and other ligands that bind to the target molecule.
  • the polypeptide is usually a polypeptide that binds to the target molecule, preferably a polypeptide that specifically binds to the target molecule. Specific binding refers to binding to a target molecule but not to a molecule other than the target molecule or weak binding.
  • the target molecule refers to a target site to be diagnosed with a radiolabeled drug, for example, a molecule present in a tissue or a cell, preferably a molecule that is specifically expressed. “Specifically expressed” refers to expression at a target site, but not at a site other than the target site, or low expression.
  • target molecule recognition element examples include a protein that is highly expressed in tissue construction accompanying inflammation, tumor cell infiltration, etc., a ligand that binds to a protein that is specifically expressed in tumor cells, and an antibody and an antigen-binding region of the antibody. Examples thereof include fragments.
  • Examples of the antibody include monoclonal antibodies such as anti-CD25 antibody and anti-CD20 antibody.
  • Examples of the antigen-binding region fragment of an antibody include, for example, a Fab fragment (hereinafter also simply referred to as “Fab”), F (ab ′) 2 fragment, F (ab) 2 fragment, and variable region fragment (hereinafter also referred to as “Fv fragment”). ).
  • the Fab fragment means an N-terminal product generated by papain degradation of an antibody and a fragment having the same domain structure.
  • the F (ab ′) 2 fragment means a fragment obtained by reducing a disulfide bond in the hinge region of F (ab ′) 2 of an antibody and a fragment having a domain structure similar to this.
  • the F (ab) 2 fragment means a dimer in which two molecules of Fab fragments are bonded to each other by a disulfide bond.
  • the Fv fragment means the smallest fragment that is an antibody fragment and has an antigen-binding activity. More specifically, examples of the antigen-binding region fragment of an antibody include an antibody against a protein specifically expressed in a specific cancer cell, and an Fab fragment or Fv fragment thereof.
  • target molecule recognition elements include cyclic pentapeptides having affinity for integrins that are highly expressed in cancer neovascular vessels, such as cyclo-Arg-Gly-Asp-D-Phe-Lys (hereinafter referred to as “c ( RGDfK) ”).
  • receptors for bisphosphonic acid, oligoaspartic acid, oligoglutamic acid and macrophages that have an affinity for hydroxyapatite, which is abundant in osteogenic cancer (bone metastasis) FMet-Leu-Phe (fMLP), a folic acid that binds to a folate receptor that is expressed in cancer cells, and derivatives thereof.
  • the target molecule recognition element is not limited to these exemplified polypeptides, and any polypeptide that binds to the target molecule can be used.
  • the target molecule recognition element may be bonded by introducing a linking group that reacts with the functional group of the compound using, for example, a thiolation reagent such as 2-iminothiolane.
  • the linking group can be introduced into the Fab fragment by adding a sulfhydryl group to the amino group in the Fab cross section by reacting the thiolation reagent under the conditions of pH 7-9.
  • a ligand having an Asn-urea-Lys site or a Glu-urea-Lys site may be used. According to the ligand, it selectively binds to a receptor of a prostate specific membrane antigen whose expression is markedly increased in prostate cancer.
  • the Asn-urea-Lys moiety is a formula: [In the formula, * is a binding site. It is a site
  • the Glu-urea-Lys moiety is a formula: [In the formula, * is a binding site. It is a site
  • a preparation for preparing a radiolabeled drug containing the compound can be provided.
  • the drug for preparing a radiolabeled drug may contain a pH adjusting agent such as an aqueous buffer, a stabilizer such as ascorbic acid and p-aminobenzoic acid, in addition to the compound.
  • Examples of the compound (2) of the present invention include compounds represented by the following formula (2).
  • L 1 is a linking group that links R 1 and P 1 ; p is 0 or 1; P 1 is a target molecule recognition element.
  • L 1 forms a bond by a functional group that can be linked to the linking group of R 1 , and also forms a bond with the target molecule recognition element.
  • L 1 is preferably iminothiol derived from 2-iminothiolane.
  • p is preferably 1.
  • P 1 is, for example, the above-described target molecule recognition element, preferably a polypeptide or other ligand that binds to the target molecule.
  • Metal complex compound (3) includes one metal selected from a radioactive metal and a radioactive atom labeled metal, Or a pharmacologically acceptable salt thereof of the present invention coordinated to a metal.
  • the radiolabeled drug containing the metal complex compound (3) and the like of the present invention may contain unreacted substances and impurities in addition to the metal complex compound (3) and the like, or a high performance liquid chromatography (HPLC) method after production.
  • purified by etc. may be included.
  • complex means a substance in which a ligand is coordinated around an atom or ion of a metal and a metal-like element, and is also called a coordination compound.
  • Coordination means that a ligand forms a coordinate bond with a central metal and is arranged around the central metal.
  • the complex is formed by a coordinate bond between a ligand and a metal. Formation of a complex of a ligand and a metal may be referred to as complex formation.
  • a coordinate bond refers to a bond in which two valence electrons participating in one bond are provided from only one atom.
  • the metal examples include 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, and 18 F—Al.
  • 18 F-Al is Al labeled with 18 F, and can be introduced into compound (2) and the like, for example, by the method described in [Bioconjugate Chem., 2014, 25, 2038-2045].
  • the metal is preferably at least one selected from the group consisting of 67 Ga, 68 Ga, 18 F—Al, 64 Cu and 67 Cu, and more preferably the group consisting of 67 Ga, 68 Ga and 18 F—Al. And more preferably at least one selected from the group consisting of 67 Ga and 68 Ga.
  • the metal is not limited to these specific examples, and any metal can be used as long as it has an appropriate radiation, radiation dose, and half-life for the purpose of diagnosis using a radiolabeled drug. From the viewpoint of reducing the influence on normal tissues and cells in radiological image diagnosis, a short half-life metal radioactive isotope is preferably used.
  • the production of the metal complex compound (3) and the like can be performed by complexing in vitro with a metal radioisotope using the above compound bonded to the target molecule recognition element as a ligand.
  • Complex formation can be performed by a simple operation using a conventionally known complex formation reaction.
  • the metal complex compound (3) of the present invention is Preferably, it has one metal selected from a radioactive metal and a radioactive atom-labeled metal, and a compound obtained by binding a target molecule recognition element to a compound represented by the formula (1) coordinated with the metal.
  • Metal complex compounds, etc. More preferably, for one compound selected from the group consisting of 67 Ga, 68 Ga, 18 F-Al, 64 Cu, and 67 Cu, a compound represented by the formula (1) coordinated to the metal, and the like A metal complex compound having a compound formed by binding a target molecule recognition element, etc.
  • the metal is preferably one selected from the group consisting of 67 Ga, 68 Ga, 18 F—Al, 64 Cu, and 67 Cu, and a compound represented by the formula (1a) coordinated to the metal, etc.
  • the metal is preferably one selected from the group consisting of 67 Ga and 68 Ga.
  • Examples of the metal complex compound (3) of the present invention include metal complex compounds represented by the following formula (3-1) or formula (3-2).
  • a 1 , m, A 2 , A 3 , n, R 1 are the same as those in the formula (1); M is 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, or 18 F—Al. ]
  • the radiolabeled drug of the present invention includes the above-mentioned radiolabeled polypeptide as an active ingredient, and as necessary, a pharmaceutical composition containing one or more kinds of pharmaceutically acceptable carriers (pharmaceutical carriers).
  • pharmaceutical carriers aqueous buffers, pH adjusters such as acids and bases, stabilizers such as ascorbic acid and p-aminobenzoic acid, excipients such as D-mannitol, isotonic agents, and preservatives Etc. can be illustrated.
  • compounds such as citric acid, tartaric acid, malonic acid, sodium gluconate, sodium glucoheptonate, etc., useful for improving the radiochemical purity may be added.
  • the radiolabeled drug of the present invention can be provided in any form of an aqueous solution, a frozen solution, and a lyophilized product.
  • the kit of this invention contains the said compound and the chemical
  • the kit of the present invention includes, for example, a compound (1), a drug containing a target molecule recognition element, and a drug containing one kind of metal selected from a radioactive metal and a radioactive atom labeled metal as separate packaging units.
  • Any of the compounds and drugs contained in the kit can contain one or more pharmaceutically acceptable carriers (pharmaceutical carriers) as described above, if necessary.
  • the compound (1) and the like of the present invention and the compound (2) obtained by binding a target molecule recognition element to the compound (1) and the like can be synthesized using a known method. Can be produced by the method described in the examples of the manual.
  • the metal complex compound (3) and the like of the present invention can be produced by using the compound (2) or the like as a ligand and complexing with a metal radioisotope in vitro. Complex formation can be performed using a known method.
  • the metal complex compound and the like of the present invention are used as, for example, a radiolabeled drug used for radiological image diagnosis.
  • radiation image diagnosis include single photon emission tomography (hereinafter simply referred to as “SPECT”), positron emission tomography (hereinafter also simply referred to as “PET”), and the like. It is done.
  • the diagnosis is not particularly limited, and is used for various diseases such as tumors, inflammations, infections, cardiovascular diseases, brain / central diseases, and radiographic diagnosis of organs / tissues, preferably cancer radiation. Used for diagnostic imaging. By selecting a target molecule recognition element according to the characteristics of the target to be diagnosed, various types of targets can be diagnosed and treated, and the radiolabeled drug of the present invention can be widely used in the field of diagnosis.
  • Examples of the administration route of the radiolabeled drug of the present invention include parenteral administration such as intravenous administration or intraarterial administration, and oral administration, and intravenous administration is preferred.
  • the administration route is not limited to these routes, and any route can be used as long as its action can be effectively expressed after administration of the radiolabeled drug.
  • the radioactivity intensity of the radiolabeled drug of the present invention is arbitrary as long as the objective can be achieved by administering the drug and the subject is exposed to the lowest possible clinical dose.
  • the radioactive intensity can be determined with reference to the radioactive intensity used in a general diagnostic method or therapeutic method using a radiolabeled drug.
  • the dose is determined in consideration of various conditions such as the patient's age, weight, appropriate radiographic imaging device, and the state of the target disease, and the radioactivity and dose considered to be capable of imaging are determined.
  • the amount of radioactivity in various metals is as follows.
  • 67 Ga it is usually assumed that it is used for SPECT, and the dose of the diagnostic agent is not particularly limited.
  • the radioactivity of 67 Ga is 1.1 MBq / kg to 1.5 MBq / kg. is there.
  • 68 Ga it is usually assumed that it is used for PET, and the dose of the diagnostic agent is 1.5 MBq / kg to 3 MBq / kg as the radioactivity of 68 Ga.
  • 18 F-Al it is usually assumed that it is used for PET, and the dosage of a diagnostic agent is 1.5 MBq to 4 MBq as a radioactive amount of 18 F.
  • the dose of diagnostic agent is 1.5 MBq / kg to 4 MBq / kg as the radioactivity of 64 Cu.
  • the capacity is 0.93 GBq / m 2 to 2.22 GBq / m 2 .
  • the dosage of diagnostic agent is 0.93GBq / m 2 ⁇ 2.22GBq / m 2 as the amount of radioactivity 67 Cu.
  • the radiolabeled drug of the present invention gives a clearer image and enables highly accurate radiological image diagnosis as compared with the conventional case.
  • Fmoc fluorenylmethoxycarbonyl group Boc: tert-butoxycarbonyl group Trt (2-Cl): 2-chlorotrityl group p-SCN-Bn-NOTA: 2-S- (4-isothiocyanatobenzyl) -1, 4,7-Triazacyclononane-1,4,7-triacetic acid Cl-Trt (2-Cl) Resin: 2-Chlorotrityl chloride resin Fmoc-Lys (Dde) -OH: N- ⁇ - (9-fluorenylmethoxycarbonyl) -N- ⁇ - [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl]- L-lysine Fmoc-Lys-OH ⁇ HCl: N- ⁇ - (9-fluorenylmethoxycarbonyl group Boc: tert-butoxycarbonyl group Trt (2-Cl): 2-
  • ADVANTEC SELECA-V Toyo Roshi Kaisha, Ltd.
  • SE-HPLC Analysis by molecular sieve HPLC
  • mice Male ddY SPF mice 6 weeks old and male BALB / c-nu / nu mice (Japan SLC, Inc.) were used.
  • Reference Example 2 Synthesis of NOTA-MIK (Bzo) In the same manner as Reference Example 1 except that Fmoc-Val-OH in Synthesis Example 2 (b) was replaced with Fmoc-Ile-OH, NOTA-MIK ( Bzo) was synthesized.
  • the filtrate was replaced with 20 mM phosphate buffer (pH 7.0) using a 10 kDa ultrafiltration membrane, and concentrated to 1 mL. Then, it refine
  • the compound was purified by a spin column method using Sephadex G-50 Fine equilibrated with 0.25 M acetic acid buffer (pH 5.5) to obtain the following compound 2-1 (hereinafter also referred to as “NOTA-MVK-Fab”).
  • the number of units derived from NOTA-MVK (mal) introduced per molecule of Fab was measured using DPS before adding iodoacetamide [Archives of Biochemistry and Biophysics, 1967, 119, 41-49] It calculated
  • Comparative Example 2 Preparation of NOTA-SCN-Fab A 0.1 M borate buffer solution (pH 9.0) was used to prepare a Fab solution (100 ⁇ L, 5.0 mg / mL). 2.25 ⁇ L of dissolved p-SCN-Bn-NOTA (5.0 mg / mL) was added and stirred at room temperature for 12 hours. After the reaction, it was purified by a spin column method using Sephadex G-50 Fine equilibrated with 0.25 M acetate buffer (pH 5.5) that had been sufficiently degassed to obtain NOTA-SCN-Fab.
  • Example 3 Preparation of 67 Ga-NOTA-MVK-Fab 67 GaCl 3 (5 ⁇ L, Fujifilm RI Pharma Co., Ltd.) was mixed with 0.25 M acetate buffer (pH 5.5, 5 ⁇ L) and allowed to stand at room temperature for 5 minutes. I put it. After mixing NOTA-MVK-Fab solution (10 ⁇ L), it was incubated at 37 ° C. for 1 hour.
  • Reference Example 5 67 Ga-NOTA-MIK except that the prepared NOTA-MVK-Fab solution (BZO) to NOTA-MIK (Bzo) solution, in the same manner as in Example 3, 67 Ga- NOTA-MIK (Bzo) was prepared. A radiochemical yield of 95% or more was confirmed by TLC, CAE, and SE-HPLC.
  • Example 4 Preparation of 64 Cu-NOTA-MVK-Fab 64 CuCl 2 (5 ⁇ L) was mixed with 0.1 M ammonium citrate buffer (pH 5.5, 5 ⁇ L) and allowed to stand at room temperature for 5 minutes. After mixing NOTA-MVK-Fab solution (10 ⁇ L), it was incubated at 37 ° C. for 1 hour. After adding 20 mM EDTA solution (20 ⁇ L), purification by spin column method using Sephadex G-50 Fine equilibrated with 0.1 M phosphorus buffer (pH 7.0), the following metal complex compound 3-2 ( Hereinafter, “ 64 Cu-NOTA-MVK-Fab” was also produced. A radiochemical yield of 95% or more was confirmed by TLC and SE-HPLC.
  • Comparative Example 5 Preparation of 64 Cu-NOTA-SCN-Fab 67 Ga-NOTA-SCN-Fab was prepared in the same manner as in Example 4 except that the NOTA-MVK-Fab solution was changed to a NOTA-SCN-Fab solution. Was made. A radiochemical yield of 95% or more was confirmed by TLC and SE-HPLC.
  • BBMVs Renal brush border membrane vesicles
  • BBMVs Renal brush border membrane vesicles
  • a 1.0 M MgCl 2 aqueous solution was added to a final concentration of 10 mM and left for 15 minutes.
  • the homogenate was then centrifuged at 1,900 g and the supernatant was further centrifuged at 24,000 g for 30 minutes.
  • the precipitate was resuspended in 6 mM Tris-HCl buffer (pH 7.1) containing 150 mM mannitol and 2.5 mM EGTA corresponding to 20 times the cortical weight, and homogenized with a Teflon (registered trademark) homogenizer (1,000 rpm, 10 strokes). .
  • 1.0 M MgCl 2 aqueous solution was added to a final concentration of 10 mM, the suspension was allowed to stand for 15 minutes, and then the homogenate was centrifuged at 1,900 g, and the supernatant was further centrifuged at 24,000 g for 30 minutes.
  • the obtained precipitate was suspended in 0.1 M phosphate buffer (pH 7.0) corresponding to 10 times the cortical weight, and homogenized again with a Teflon homogenizer (1,000 rpm, 10 strokes). The homogenate was then centrifuged at 24,000 g for 30 minutes to obtain BBMVs as a precipitate.
  • BBMVs precipitate was resuspended in 0.1 M phosphate buffer (pH 7.0), and passed through a 0.4 ⁇ 19 mm needle 10 times to keep the vesicle size constant.
  • the protein concentration was diluted to 10 mg / mL.
  • ⁇ -galactosidase activity which is a lysosomal marker enzyme, was measured using p-nitrophenyl- ⁇ -D-galacto-pyranoside to evaluate contamination of the lysosomal fraction.
  • the activity of ⁇ -glutamyl transferase and aminopeptidase was measured using L- ⁇ -glutamyl-p-nitroanilide and L-leucine-p-nitroanilide.
  • Incubation test Incubation experiments of BBMVs and 67 Ga-NOTA-MVK (Bzo) were performed as follows. BBMVs (10 ⁇ L) prepared at a protein concentration of 10 mg / mL were preincubated at 37 ° C. for 10 minutes. 67 Ga-NOTA-MVK (Bzo) was redissolved in D-PBS ( ⁇ ) after removing excess ligand by RP-HPLC. 67 Ga-NOTA-MVK (Bzo) solution (10 ⁇ L) was added to the BBMVs solution, and after incubation at 37 ° C. for 2 hours, a part of the solution was collected and analyzed by RP-TLC.
  • each enzyme inhibitor (5 ⁇ L) was added to BBMVs (10 ⁇ L) that had been pre-incubated in the same way to a final concentration of 1 mM, and the mixture was incubated at 37 o for 10 minutes. After incubation with C, 67 Ga-NOTA-MVK (Bzo) solution (5 ⁇ L) was added.
  • MGTA an inhibitor of carboxylpeptidase M, cilastatin, an inhibitor of renal dipeptidase, captpril of angiotensin-converting enzyme, and phosphoramidon, a specific inhibitor of neutral endopeptidase
  • 67 Ga-NOTA-MVK (Bzo) and 67 Ga-NOTA-MIK (Bzo) were compared by the same method as described above, and analyzed by RP-HPLC and TLC.
  • FIG. 1 shows the results of studies on the stability of radioactive metal-labeled Fab in mouse plasma.
  • 67 Ga-NOTA-MVK-Fab results are “MVK”
  • 67 Ga-NOTA-MI-Fab results are “MI”
  • 67 Ga-NOTA-SCN-Fab results are “SCN”. Represent (same below). As a result, more than 95% of the radioactivity was present in the Fab fraction even after 24 hours.
  • Table 1 shows the time course of the radioactivity distribution in the body after administration of 67 Ga-NOTA-MVK-Fab, 67 Ga-NOTA-MI-Fab and 67 Ga-NOTA-SCN-Fab to normal mice.
  • FIG. 2 shows the time course of (a) renal radioactivity (time-radiation dose curve in the kidney) and (b) renal blood ratio of radioactivity.
  • 67 Ga-NOTA-SCN-Fab showed high radioactivity in the kidney from the early stage of administration, and a high radioactivity of 63% ID / g was observed even 6 hours after administration.
  • 67 Ga-NOTA-MI -Fab showed a maximum value of 44% ID / g at 1 hour after administration, but then decreased over time, and after 6 hours, the radioactivity of 23% ID / g in the kidney was observed.
  • 67 Ga-NOTA-MVK-Fab showed a low level of accumulation in the kidney from the early stage of administration, and showed a maximum value of 20% ID / g after 30 minutes. After time, 8% ID / g was significantly lower than 67 Ga-NOTA-MI-Fab and 67 Ga-NOTA-SCN-Fab.
  • 67 Ga-NOTA-MVK-Fab was also significantly lower in the renal blood ratio than 67 Ga-NOTA-MI-Fab and 67 Ga-NOTA-SCN-Fab.
  • D-PBS (-) 100 ⁇ L + EtOH 200 ⁇ L 300 ⁇ L of 66 wt% EtOH solution
  • FIG. 3 shows urinary radioactivity up to 6 hours after administration of (a) 67 Ga-NOTA-MVK-Fab, (b) 67 Ga-NOTA-MI-Fab, and (c) 67 Ga-NOTA-SCN-Fab.
  • the analysis result by SE-HPLC is shown. In SE-HPLC analysis, 70-80% ID / g of radioactivity was present in the low molecular fraction with a retention time of 24-25 minutes.
  • FIG. 4 shows urinary radioactivity up to 6 hours after administration of (a) 67 Ga-NOTA-MVK-Fab, (b) 67 Ga-NOTA-MI-Fab, and (c) 67 Ga-NOTA-SCN-Fab.
  • the 67 Ga-NOTA-Bn-Lys preparation was synthesized according to the method described in “Bioconjugate Chem., 1997, 8, 365-369”. Above, in analysis by SE-HPLC as shown in Figure 3 Analysis of radioactivity in the urine, most of the radioactivity was excreted in the low molecular fraction from the results of RP-HPLC as shown in FIG. 4, 67 Ga-NOTA -MVK-Fab shows that the main radioactivity in the low molecular fraction is 67 Ga-NOTA-Bn-Met.
  • the radioactive metal-labeled Fabs prepared in Examples and Comparative Examples prepared by the above method were diluted with phosphate buffered saline (1 mM, pH 7.4).
  • Each radioactive metal-labeled Fab solution (0.3 ⁇ Ci / 100 ⁇ L / animal) prepared to a Fab concentration of 5 ⁇ g / 100 ⁇ L was administered from the tail vein of the subcutaneous tumor model mouse.
  • Three hours and 6 hours after administration were sacrificed for 5 mice in each group, blood and organs of interest were collected, weight After measuring, radioactivity was measured by an autowell gamma system.
  • Table 2 shows the in vivo radioactivity distribution after administration of 67 Ga-NOTA-MVK-Fab, 67 Ga-NOTA-MI-Fab and 67 Ga-NOTA-SCN-Fab to SY subcutaneous tumor model mice.
  • FIG. 5 shows the tumor kidney ratio of 67 Ga-NOTA-MVK-Fab, 67 Ga-NOTA-MI-Fab and 67 Ga-NOTA-SCN-Fab.
  • 67 Ga-NOTA-MVK-Fab showed a high tumor-kidney ratio of 0.63.
  • FIG. 6 shows SPECT / CT images after administering 67 Ga-NOTA-MVK-Fab, 67 Ga-NOTA-MI-Fab, and 67 Ga-NOTA-SCN-Fab to SY subcutaneous tumor model mice.
  • FIG. 6 shows SPECT / CT images 3 hours after each 67 Ga-labeled Fab solution was administered to SY subcutaneous tumor model mice. Tumor (T), kidney (K), bladder (B) are shown. At 3 hours after administration, 67 Ga-NOTA-MVK-Fab had a low accumulation in the kidney, and the tumor was clearly imaged.
  • 67 Ga-NOTA-MI-Fab and 67 Ga-NOTA-SCN-Fab although tumors were imaged, high radioactivity was also observed in the kidney. As described above, radiolabeled drugs have low accumulation in the kidney and can improve the sensitivity and accuracy of radiographic diagnosis.
  • PET imaging 64 Cu-NOTA-MVK-Fab and 64 Cu-NOTA-Fab were administered to normal mice (0.09-0.14 mCi), and PET (Inveon, Siemens Medical Solutions, USA) was imaged over 30 minutes after 3 hours.
  • Figure 7 shows 64 Cu-NOTA-MVK-Fab A PET image after 3 hours is shown when 64 Cu-MVK-Fab (shown in the figure) and 64 Cu-NOTA-Fab (shown as 64 Cu-SCN-Fab in the figure) are administered to normal mice.
  • 64 Cu -NOTA-MVK-Fab has low accumulation in the kidney.
  • 64 Ga-NOTA-SCN-Fab high radioactivity was observed in the kidney. As described above, it can be seen that the radioactively labeled drug related to 64 Cu -NOTA-MVK-Fab has a low accumulation in the kidney.

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Abstract

La présente invention concerne un composé, etc. à partir duquel est obtenu un médicament radiomarqué apte à réduire l'accumulation dans les reins à partir d'une administration précoce. [1] Un composé, etc. représenté par la formule (1) ; [2] un composé, etc. obtenu par liaison d'un élément de reconnaissance de molécule cible au composé, etc. décrit en [1] ci-dessus ; [3] un composé de complexe métallique, etc. ayant un type de métal choisi parmi des métaux radioactifs et des métaux marqués par un atome radioactif, et le composé, etc. décrit en [1] ou [2] ci-dessus coordonné au métal ; [4] un médicament pour préparer un médicament radiomarqué comprenant le composé, etc. décrit en [1] ou [2] ci-dessus ; [5] une utilisation pour produire un médicament radiomarqué du composé, etc. décrit en [1] ou [2] ci-dessus ; [6] un médicament radiomarqué comprenant le composé complexe métallique, etc. décrit en [3] ci-dessus ; et [7] un agent de diagnostic d'imagerie radiologique comprenant le complexe métallique, etc. décrit en [3] ci-dessus.
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US16/081,141 US10960089B2 (en) 2016-03-01 2017-02-28 Radiolabeled drug
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KR20210113201A (ko) 2019-01-07 2021-09-15 아스텔라스세이야쿠 가부시키가이샤 배위자 및 CEACAM5 항체 Fab 프래그먼트를 포함하는 복합체
CN113271973A (zh) * 2019-01-07 2021-08-17 安斯泰来制药株式会社 包含配体和CEACAM5抗体Fab片段的复合物
JPWO2020145227A1 (ja) * 2019-01-07 2021-11-11 アステラス製薬株式会社 配位子、スペーサー、ペプチドリンカーおよび生物分子からなる複合体
CN113301920A (zh) * 2019-01-07 2021-08-24 安斯泰来制药株式会社 包含配体、间隔物、肽接头和生物分子的复合物
WO2020145227A1 (fr) 2019-01-07 2020-07-16 アステラス製薬株式会社 Composite constitué d'un ligand, d'un espaceur, d'un lieur peptidique et d'une biomolécule
WO2020145228A1 (fr) 2019-01-07 2020-07-16 アステラス製薬株式会社 Composite constitué d'un ligand et d'un fragment fab d'un anticorps ｃｅａｃａｍ５
KR20210113202A (ko) 2019-01-07 2021-09-15 아스텔라스세이야쿠 가부시키가이샤 배위자, 스페이서, 펩티드 링커 및 생물 분자를 포함하는 복합체
JP7414370B2 (ja) 2019-01-07 2024-01-16 アステラス製薬株式会社 配位子、スペーサー、ペプチドリンカーおよび生物分子からなる複合体
WO2021177390A1 (fr) 2020-03-04 2021-09-10 日本メジフィジックス株式会社 Composé et composé de marquage radioactif
CN112250732A (zh) * 2020-10-28 2021-01-22 西安华牧生物科技有限责任公司 基于酶切原理可降低放射性肾浓聚的探针及其制备方法
WO2022186311A1 (fr) 2021-03-04 2022-09-09 日本メジフィジックス株式会社 Composé et composé de marquage radioactif
WO2023104794A1 (fr) 2021-12-06 2023-06-15 Paul Scherrer Institut Technologie à lieur pour réduire la rétention rénale

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US20190091353A1 (en) 2019-03-28
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CN108699108A (zh) 2018-10-23
EP3424940A4 (fr) 2019-10-30
US10960089B2 (en) 2021-03-30
JP6966741B2 (ja) 2021-11-17
CN108699108B (zh) 2022-04-08
HK1257541A1 (zh) 2019-10-25

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